KR101520337B1 - Method for producing 2,2-difluoroethylamine derivatives by imine hydrogenation - Google Patents

Abstract

상기 식에서,
A 래디칼은 명세서에 정의된 바와 같다.A process for the preparation of a 2,2-difluoroethylamine derivative, wherein a compound of formula (IV) is hydrogenated with a corresponding 2,2-difluoroethylamine derivative of formula (III)

In this formula,
A radicals are as defined in the specification.

Description

[0001] The present invention relates to a process for producing 2,2-difluoroethylamine derivatives by imine hydrogenation,

The present invention relates to a process for preparing 2,2-difluoroethanamine derivatives from 2,2-difluoroethylimine derivatives. The present invention also provides a 2,2-difluoroethylimine derivative used as a starting compound in the process according to the present invention, a process for its preparation and its use for preparing 2,2-difluoroethylamine derivatives .

2,2-difluoroethylamine derivatives are important intermediates for the production of agrochemical active ingredients. For example, a 2,2-difluoroethylamine derivative suitable for synthesizing a 4-aminobut-2-enolamide compound as a pesticidal active enaminocarbonyl compound may be used. Enaminocarbonyl compounds having 2,2-difluoroethylamino units are known, for example, from International Patent Applications WO 2007/115644 and WO 2007/115646.

WO 2007/115644 discloses a process for the preparation of 2,2-difluoroethylamine derivatives, for example compounds of formula (IIIa), by alkylation of amines of formula (Ia) with optionally substituted chloromethylpyridines of formula (IIa) (DE 10 2006 015 467A, starting compound; compound of formula (III); III-1: N - [(6-chloropyridin-3- yl) methyl] -2,2-di Fluoroethyl-1-amine < / RTI >

Scheme 1:

A disadvantage of this process is that the yield is as low as 53%, possibly due to possible multiple alkylation of nitrogen atoms. This degree of multiple alkylation can be reduced by using excess amine, but is not economical for expensive amines.

According to the prior art, it is an object of the present invention to provide a process for producing a 2,2-difluoroethylamine derivative which is simple and inexpensive to carry out. The 2,2-difluoroethylamine derivative obtainable by such an intended method should preferably be obtained in high yield and high purity. More particularly, the intended method should be able to obtain the target compound of interest without the need for complicated purification methods.

This object is achieved by a process for the preparation of 2,2-difluoroethylamine derivatives.

The process according to the invention is characterized in that the 2,2-difluoroethylimine derivative of formula (IV) is hydrogenated to the corresponding target compound of formula (III) according to the following scheme:

Scheme 2:

Accordingly, the present invention relates to the preparation of the 2,2-difluoroethylamine derivative of formula (III) by hydrogenating the corresponding 2,2-difluoroethylimine derivative of formula (IV). The desired 2,2-difluoroethylamine derivative of formula (III) is obtained in good yield and high purity under the reaction conditions and the preferred reaction conditions, which are described in detail below, by solving the above-mentioned disadvantages of the process according to the invention . The objective compound is generally obtained in a purity that does not require extensive after-treatment of the direct reaction product. By the process according to the invention, the yield can be improved as compared to the process known from the prior art of alkylating an amine according to Scheme 1. Also, the purity of the target compound of interest in the process according to the invention is considerable without polyalkylation.

In the context of the present invention, derivatives refer to similar structures derived from the corresponding organic base structures (units), i.e., 2,2-difluoroethylamine derivatives include, for example, 2,2-difluoroethylamine ≪ RTI ID = 0.0 > and / or < / RTI >

In the above-mentioned formulas (III) and (IV), the radical A is defined as follows:

Pyrid-2-yl or pyrid-4-yl or pyrid-3-yl optionally substituted by fluorine, chlorine, bromine, methyl, trifluoromethyl or trifluoromethoxy, Pyridazin-3-yl, pyrazin-3-yl, 2-chloropyrazin-5-yl, optionally substituted by chlorine or methyl, 5-day,

C ₁ -C ₃ -alkyl (optionally substituted by fluorine and / or chlorine), C ₁ -C ₃ -alkylthio (optionally substituted by fluorine and / or chlorine), fluorine, chlorine, bromine, Pyrazolyl, thiophenyl, oxazolyl, isoxazolyl, 1, 2, 3, 4, 5, 6 or 7 substituents optionally substituted by C ₁ -C ₃ -alkylsulfonyl (optionally substituted by fluorine and / or chlorine) 4-oxadiazolyl, isothiazolyl, 1,2,4-triazolyl or 1,2,5-thiadiazolyl,

·

ego,

From here,

X is halogen, alkyl or haloalkyl,

Y is halogen, alkyl, haloalkyl, haloalkoxy, azido or cyano.

Hereinafter, preferred, particularly preferred or very particularly preferred definitions of A radicals depending on the abovementioned formulas (III) and (IV) are described:

A is preferably 6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid- 6-chloro-1,4-pyridazin-3-yl, 6-methyl-1,4-pyridazin-3- Chloro-1, 3-thiazol-5-yl or 2-methyl-1,3-thiazol-5-yl, 2- chloropyrimidin-5-yl, 2-trifluoromethylpyrimidine 5-yl, 5,6-difluoropyrid-3-yl, 5-chloro-6-fluoropyrid- 6-chloropyrid-3-yl, 5,6-dichloropyrid-3-yl, 5-bromo-6- Chloro-6-bromopyrid-3-yl, 5-chloro-6-bromopyrid- 5-chloro-6-iodopyrid-3-yl, 5-bromo-6-iodopyrid- - iodopyrid-3-yl, Methyl-6-fluoropyrid-3-yl, 5-methyl-6-chloropyrid- 5-difluoromethyl-6-fluoropyrid-3-yl, 5-difluoromethyl-6-chloropyrid- -Bromopyrid-3-yl and 5-difluoromethyl-6-iodopyrid-3-yl.

A is more preferably 6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid- Chloro-1, 3-thiazol-5-yl, 2-chloropyrimidin-5-yl, 5-fluoro-6-chloropyrid- 5-chloro-6-bromopyrid-3-yl, 5-bromo-6-chloropyrid- 5-chloro-6-iodopyrid-3-yl and 5-difluoromethyl-6-chloropyrid- Yl-3-yl.

A is most preferably 6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-chloro-1,4-pyridazin- Yl, 5-fluoro-6-chloropyrid-3-yl and 5-fluoro-6-bromopyrid-3-yl.

The term "alkyl ", when used alone or in combination with other terms such as, for example, haloalkyl, is understood to mean a radical of a saturated aliphatic hydrocarbon group having from 1 to 12 carbon atoms which may be branched or unbranched. Examples of C ₁ -C ₁₂ -alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n- pentyl, isopentyl, neopentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-pentyl groups such as methyl, ethyl, Of these alkyl radicals, C ₁ -C ₆ -alkyl radicals are particularly preferred, in particular C ₁ -C ₄ -alkyl radicals are preferred.

According to the present invention, the term "aryl" shall be understood to mean aromatic radicals having 6 to 14 carbon atoms, with phenyl being preferred.

The term "arylalkyl" shall be understood to mean a combination of an "aryl" and an "alkyl" radical as defined in accordance with the present invention wherein the radical is generally bonded through an alkyl group, methylbenzyl, and benzyl is particularly preferable.

In the context of the present invention, it is to be understood that a halogen-substituted radical, such as haloalkyl, means a radical of one or more halogenated with the maximum possible number of substituents. When polyhalogenated, the halogen atoms may be the same or different. Halogen is fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.

In the context of the present invention, the term "alkoxy ", when used alone or in combination with other terms such as haloalkoxy, is understood to mean an O-alkyl radical, As defined.

Optionally substituted radicals can be mono- or polysubstituted, and when it is polysubstituted, the substituents may be the same or different.

The 2,2-difluoroethylimine derivative of formula (IV) can be hydrogenated to the corresponding amine of formula (III) using the reducing agent itself known to those skilled in the art. E.g,

- complex hydrides,

- non-adherent metal or semi-metal hydrides,

- Na / EtOH, or

- by catalytic hydrogenation

It is possible to perform hydrogenation.

It should be understood that complex hydrides generally refer to charged metal complexes containing at least one hydride ligand. Examples thereof include lithium aluminum hydride (LiAlH ₄ ), LiAlH (O-tert-butyl) ₃ , LiAlH (O-methyl) ₃ , NaAlEt ₂ H ₂ , sodium borohydride (NaBH ₄ ) and the like. Examples of the non-adherent metal and semimetal hydride include AlH ₃ , DIBAL-H (AlH (isobutyl) ₂ ), and the like. Among them, it is particularly preferable to use sodium borohydride (NaBH ₄ ). The reaction with the metal complex hydride or the non-adherent metal or the semi-metal hydride can be carried out under reduced pressure at a standard pressure or elevated pressure and at a temperature of -30 to 150 ° C, preferably -10 to 60 ° C.

When catalytic hydrogenation is used to reduce the compound of formula (IV), the catalyst used may be any desired hydrogenation catalyst. Suitable catalysts optionally contain one or more metals from Groups 8-10 of the Periodic Table on any desired inorganic support. Useful catalysts include, for example, noble metal catalysts such as ruthenium catalysts, palladium catalysts, platinum catalysts and rhodium catalysts, Raney nickel catalysts and Lindlar catalysts. In addition to these hydrogenation catalysts, it is also possible to carry out the hydrogenation over a homogeneous catalyst, for example a Wilkinson catalyst. Corresponding catalysts may also be applied in the form in which they are applied to the supported form, for example carbon (inert or activated carbon), aluminum oxide, silicon dioxide, zirconium dioxide or carbon dioxide. Corresponding catalysts are known per se to those skilled in the art. Raney nickel catalysts are particularly preferred.

Catalytic hydrogenation can be carried out under hydrogen gas atmosphere at standard pressure or under reduced pressure in an autoclave. The hydrogen gas atmosphere also includes an inert gas, such as argon or nitrogen. The catalytic hydrogenation is preferably carried out at a temperature of from 10 to 60 캜, more preferably from 20 to 40 캜. The hydrogen pressure is typically 0.1 to 50 bar, preferably 0.1 to 30 bar.

Additional reagents and hydrogenation conditions used in the hydrogenation of imines are described in Harada, in Patai, "The chemistry of the Carbon-Nitrogen Double Bond ", pages 276-293; And Rylaender, "Catalytic Hydrogenation over Platinum Metals ", pages 291-303, Academic Press, New York, 1967.

In general, it is advantageous to carry out the process according to the invention for imine hydrogenation in the presence of a solvent (diluent). The solvent is advantageously used in an amount such that the reaction mixture can be efficiently stirred over the pre-reduction step. Solvents useful for carrying out the process according to the invention comprise all organic solvents which are inert under the reaction conditions and the type of solvent used depends on the manner in which the reduction is carried out, more particularly the type of reducing agent.

Examples include halocarbons such as chlorohydrocarbons such as tetrachlorethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichlorethylene, pentachloroethane, difluorobenzene, 2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, chlorotoluene, trichlorobenzene; Alcohols such as methanol, ethanol, isopropanol, butanol; Examples of the solvent include ethers such as ethyl propyl ether, methyl tert-butyl ether, methyl n -butyl ether, anisole, phenetole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, Propyl ether, di- n -butyl ether, diisobutyl ether, diisobutyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichlorodi Ethyl ethers and polyethers of ethylene oxide and / or propylene oxide; Amines such as trimethyl-, triethyl-, tripropyl-, tributylamine, N -methylmorpholine, pyridine, alkylated pyridine and tetramethylenediamine; Industrial hydrocarbons which may be substituted by aliphatic, alicyclic or aromatic hydrocarbons such as pentane, n-hexane, n-heptane, n-octane, nonane and fluorine and chlorine atoms such as methylene chloride, dichloromethane, trichloromethane, , Fluorobenzene, chlorobenzene or dichlorobenzene; Such as so-called white spirit, having a boiling point in the range of, for example, 40 to 250 DEG C, cement, petroleum fractions in the boiling range 70 to 190 DEG C, cyclohexane, methylcyclohexane, petroleum ether, ligroin, , Benzene, toluene, chlorobenzene, bromobenzene, nitrobenzene, xylene; Esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, and dimethyl carbonate, dibutyl carbonate or ethylene carbonate; And aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol.

Of the above-mentioned solvents, alcohols, especially methanol and ethanol, especially methanol, are particularly preferred.

The amount of solvent used can vary within wide limits. In general, a solvent in an amount of 1 to 50 times, more preferably 2 to 40 times, particularly 2 to 30 times, based on 2,2-difluoroethylimine of the formula (IV) used in each case is used.

In addition, it is particularly preferable to use sodium borohydride (NaBH ₄ ) as a hydrogenating agent and a combination of an alcohol, particularly methanol, as a solvent.

The reaction of the present invention is in particular may be performed using a system of sodium borohydride (NaBH ₄₎ and methanol, as follows: will be added in addition with the first immigrants to the alcohol, and cooling the sodium borohydride. The mixture is then stirred at a temperature of 30 to 50 DEG C and then about 1 to 3 equivalents of water are added based on the amount of alcohol. Subsequently, extraction is carried out in an ordinary manner using an organic solvent.

Hydrogenation is generally carried out under reaction conditions (pressure, temperature, chemical amount, etc.) in which the imine group is hydrogenated to a saturated group, while the other functional groups in the molecule remain unchanged.

Post-treatment (purification) and separation of the hydrogenated imine can be performed, for example, by crystallization and / or distillation.

The present invention also relates to the use of a compound of formula (IV) for the preparation of a compound of formula (III) as described in the above-mentioned process.

The compounds of formula (IV) required for the present invention can be obtained by reacting an aldehyde of formula (VI) with 2,2-difluoroethylamine to give a compound of formula (IV) by condensation:

In this formula,

A is as defined above.

The 2,2-difluoroethylamine required for this reaction is commercially available and can be prepared by literature methods (J. Medicinal Chemistry (1989), 32 (5), 957-961).

Aldehydes of formula (II) are either commercially available or can be prepared by literature methods (for example, 6-methyl nicotinaldehyde: EP 0 104 876 A2; 2-chloropyrazine-5-carboxaldehyde: DE 3314196 A1).

In some cases, it is also possible to add an acid to the reaction as a catalyst to obtain the compound of formula (IV). Examples thereof include acetic acid, p-toluenesulfonic acid and trifluoroacetic acid. Acetic acid is preferably used.

When such a catalyst is used, the amount thereof may be from 0.01 to 10% by weight based on the amount of 2,2-difluoroethylamine used.

In a preferred embodiment of the present invention, 2,2-difluoroethylamine is used in the form of a salt. Thereby, Lewis acid addition can be eliminated or reduced. Useful salts include, for example, hydrochloride, acetate or sulfate.

 The reaction for preparing the compound of formula (IV) may also be carried out in such a way that the water formed in the reaction between the amine and the aldehyde is removed from the reaction by condensation. This is possible, for example, by using water-binding agents such as sodium sulfate, magnesium sulfate or molecular sieves, or by using a water separator.

 The reaction for preparing the compound of formula (IV) can generally be carried out under reduced pressure, standard pressure or elevated pressure. The temperature of use may likewise vary depending on the material used, and those skilled in the art will readily be able to determine it with routine experimentation. For example, the reaction for preparing the compound of formula (IV) may be carried out at a temperature of -20 to 200 占 폚, preferably 10 to 100 占 폚. It is particularly preferred to carry out the reaction at standard pressure and at a temperature of from 10 to 100 < 0 > C.

The reaction for preparing imines of formula (IV) may also be carried out in the presence of a solvent (diluent). Even in this process step, the solvent is preferably used in an amount such that the reaction mixture can be efficiently stirred over the pre-reduction step. Solvents useful for carrying out the process according to the invention for preparing substituted 2,2-difluoroethylimines of the formula (IV) include all organic solvents which are inert under the reaction conditions.

Examples include halocarbons such as chlorohydrocarbons such as tetrachlorethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichlorethylene, pentachloroethane, difluorobenzene, 2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, chlorotoluene, trichlorobenzene; Alcohols such as methanol, ethanol, isopropanol, butanol; Examples of the solvent include ethers such as ethyl propyl ether, methyl tert-butyl ether, methyl n -butyl ether, anisole, phenetole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, Propyl ether, di- n -butyl ether, diisobutyl ether, diisobutyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, dichlorodiethyl ether and ethylene oxide And / or polyethers of propylene oxide; Nitro hydrocarbons such as nitromethane, nitroethane, nitropropane, nitrobenzene, chloronitrobenzene, o-nitrotoluene; But are not limited to, nitriles such as acetonitrile, methylnitrile, propionitrile, butyronitrile, isobutyronitrile, benzonitrile, phenylnitrile, m-chlorobenzonitrile and, for example, tetrahydrothiophene dioxide and dimethylsulfoxide, Compounds such as side, dipropylsulfoxide, benzylmethylsulfoxide, diisobutylsulfoxide, dibutylsulfoxide, diisobutylsulfoxide; Sulfone such as dimethyl sulfone, diethyl sulfone, dipropyl sulfone, dibutyl sulfone, diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone and pentamethylene sulfone; For example, aliphatic, alicyclic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane and industrial hydrocarbons which may be substituted by fluorine and chlorine atoms such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, Benzene or dichlorobenzene; Cement, a petroleum fraction with a boiling point in the range of 70 to 190 占 폚, cyclohexane, methylcyclohexane, petroleum ether, ligroin, octane, benzene, toluene having a boiling range of, for example, 40 to 250 占 폚, , Chlorobenzene, bromobenzene, nitrobenzene, and xylene. Of the above-mentioned solvents, xylene, chlorobenzene, cyclohexane and toluene are particularly preferred.

In yet another embodiment, the reaction of the amine with the aldehyde may be carried out in the material.

If the reaction is carried out in a solvent, the solvent may be removed by distillation after the reaction has ended. This can be done at room temperature or elevated temperature under standard pressure or reduced pressure. The mixture can also lead directly to hydrogenation, which is particularly advantageous in view of the economics. In such an embodiment of the process according to the invention, the post-treatment of 2,2-difluoroethylimine is omitted.

The invention further provides compounds of formula (IV) used as intermediates in preparing the target compounds of formula (III): < EMI ID =

In this intermediate, substituent A is generally defined as:

Pyrid-2-yl or pyrid-4-yl or pyrid-3-yl optionally substituted by fluorine, chlorine, bromine, methyl, trifluoromethyl or trifluoromethoxy, Pyridazin-3-yl, pyrazin-3-yl, 2-chloropyrazin-5-yl, optionally substituted by chlorine or methyl, 5-day,

C ₁ -C ₃ -alkyl (optionally substituted by fluorine and / or chlorine), C ₁ -C ₃ -alkylthio (optionally substituted by fluorine and / or chlorine), fluorine, chlorine, bromine, Pyrazolyl, thiophenyl, oxazolyl, isoxazolyl, 1, 2, 3, 4, 5, 6 or 7 substituents optionally substituted by C ₁ -C ₃ -alkylsulfonyl (optionally substituted by fluorine and / or chlorine) 4-oxadiazolyl, isothiazolyl, 1,2,4-triazolyl or 1,2,5-thiadiazolyl,

·

ego,

From here,

X is halogen, alkyl or haloalkyl,

Y is halogen, alkyl, haloalkyl, haloalkoxy, azido or cyano.

In the following, preferred, particularly preferred or very particularly preferred definitions of the A radicals present in the abovementioned formulas (III) and (IV) are mentioned:

A is preferably 6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid- 6-chloro-1,4-pyridazin-3-yl, 6-methyl-1,4-pyridazin-3- Chloro-1, 3-thiazol-5-yl or 2-methyl-1,3-thiazol-5-yl, 2- chloropyrimidin-5-yl, 2-trifluoromethylpyrimidine 5-yl, 5,6-difluoropyrid-3-yl, 5-chloro-6-fluoropyrid- 6-chloropyrid-3-yl, 5,6-dichloropyrid-3-yl, 5-bromo-6- Chloro-6-bromopyrid-3-yl, 5-chloro-6-bromopyrid- 5-chloro-6-iodopyrid-3-yl, 5-bromo-6-iodopyrid- - iodopyrid-3-yl, Methyl-6-fluoropyrid-3-yl, 5-methyl-6-chloropyrid- 5-difluoromethyl-6-fluoropyrid-3-yl, 5-difluoromethyl-6-chloropyrid- -Bromopyrid-3-yl and 5-difluoromethyl-6-iodopyrid-3-yl.

A is more preferably 6-fluoropyrid-3-yl, 6-chloropyrid-3-yl, 6-bromopyrid- Chloro-1, 3-thiazol-5-yl, 2-chloropyrimidin-5-yl, 5-fluoro-6-chloropyrid- 5-chloro-6-bromopyrid-3-yl, 5-bromo-6-chloropyrid- 5-chloro-6-iodopyrid-3-yl and 5-difluoromethyl-6-chloropyrid- Yl-3-yl.

A is most preferably 6-chloropyrid-3-yl, 6-bromopyrid-3-yl, 6-chloro-1,4-pyridazin- Yl, 5-fluoro-6-chloropyrid-3-yl and 5-fluoro-6-bromopyrid-3-yl.

The compound of formula (IV) may be used as a reactant for preparing the 2,2-difluoroethylamine derivative of formula (III).

From the compounds of formula (III) obtained by the process according to the invention, it is possible to use compounds containing 2,2-difluoroethylamino units, for example in International Patent Applications WO 2007/115644 and WO 2007/115646 Enzymatically active aminocarbonyl compounds as described can be prepared.

For this purpose, a compound of formula (III) can be alkenylated on a secondary amine nitrogen, for example, by reaction with tetronic acid or a derivative thereof:

The corresponding reaction is described in detail in Scheme I of DE 10 2006 015 467, which directly provides the aminocarbonyl compound with insecticidal activity.

The present invention will be described in detail with reference to the following examples, but the examples should not be construed as limiting the present invention.

Preparation Example:

Example 1

To a solution of 74.34 g of 6-chloropyridine-3-carbaldehyde in 46 g of toluene was added 41.8 g of 2,2-difluoroethylamine at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Then 120 g of anhydrous magnesium sulfate was added and the mixture was stirred at 50 DEG C for a further 5 hours. The reaction mixture was cooled to room temperature, filtered, and the filter residue was washed with toluene. The solvent was removed under reduced pressure to obtain 100.2 g of N - [(6-chloropyridin-3-yl) methylidene)] - 2,2-difluoroethylimine with a purity of 95.5% .

_{^{1 H NMR (CDCl 3, 298K}} ) δ: 4.05 m (2H), 6.5 t (1H, C H F 2), 7.63 d (1H), 8.20 d (1H), 8.56 s (1H), 8.75 d (1H ).

Example 2

To a solution of 74 g of N - [(6-chloropyridin-3-yl) methylidene)] - 2,2-difluoroethylimine (obtained from example 1) in 343 g ethanol was added 5 g of Raney nickel The catalyst was added and hydrogenation was carried out at room temperature with 20 bar of hydrogen for 24 hours. The catalyst was filtered off, the residue was washed with 100 ml of ethanol and then the solvent was removed under reduced pressure. 71.4 g of N - [(6-chloropyridin-3-yl) methyl)] - 2,2-difluoroethylamine was obtained with a purity of 95% (corresponding to a yield of 94%).

NMR (d-DMSO): [delta] H (s, 8.35 ppm); 1H (dd, 7.8 ppm); 1H (d, 7.46 ppm); 1H (tt, 6.02 ppm); 2H (s, 3.8 ppm); 2H (td, 2.9 ppm).

Example 3

To a solution of 5 g of N - [(6-chloropyridin-3-yl) methylidene)] - 2,2-difluoroethylimine in 23 g ethanol was added in portions 1.1 g of sodium borohydride, Was stirred at room temperature. The mixture was then heated briefly to 50 < 0 > C and then poured into 100 ml of water. The mixture was extracted twice with 100 ml of methylene chloride each time, and the organic phase was combined and concentrated under reduced pressure. 4.5 g of N - [(6-chloropyridin-3-yl) methyl)] - 2,2-difluoroethylamine was obtained with a purity of 93% (corresponding to a yield of 86%).

NMR data: see Example 2.

Claims (6)

The 2,2-difluoroethylamine derivative of the formula (IV) is characterized in that the 2,2-difluoroethylamine derivative of the formula (IV) is hydrogenated with the corresponding 2,2-difluoroethylamine derivative of the formula : ≪

In the above reaction formula,
The radicals A of formulas (III) and (IV) are defined as follows:
Pyrid-2-yl or pyrid-4-yl or pyrid-3-yl optionally substituted by fluorine, chlorine, bromine, methyl, trifluoromethyl or trifluoromethoxy,
·

ego,
From here,
X is halogen, C ₁ -C ₄ -alkyl or halo-C ₁ -C ₄ -alkyl,
Y is halogen, C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkoxy, azido or cyano,
Wherein the hydrogenation is carried out using a complex hydride, a non-adherent metal or a semimetal hydride, Na / EtOH, or is carried out by catalytic hydrogenation. delete Process for preparing a compound of formula (IV), characterized in that an aldehyde of formula (VI) is reacted with 2,2-difluoroethylamine:

In this formula,
A is as defined in claim 1. A process according to claim 1, wherein the compound of formula (IV) obtained by the process according to claim 3 is used as starting compound. The compound of formula (IV)

In this formula,
A radicals are defined as follows:
Pyrid-2-yl or pyrid-4-yl or pyrid-3-yl optionally substituted by fluorine, chlorine, bromine, methyl, trifluoromethyl or trifluoromethoxy,
·

ego,
From here,
X is halogen, C ₁ -C ₄ -alkyl or halo-C ₁ -C ₄ -alkyl,
Y is halogen, C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkoxy, azido or cyano. The compound of formula (IV) according to claim 5 for the preparation of a compound of formula (III) by the process according to claim 1.